The present invention relates generally to MR spectroscopy, and more particularly, to a technique that is capable of segregating metabolite signals for improved clinical analysis.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, or “longitudinal magnetization”, Mz, may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment Mt. A signal is emitted by the excited spins after the excitation signal B1 is terminated and this signal may be received and processed to form an image.
When utilizing these signals to produce images, magnetic field gradients (Gx Gy and Gz) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
The use of nuclear magnetic resonance imaging for the determination of individual chemical compounds is known as MR spectroscopy (MRS). The underlying principle of MRS is that atomic nuclei are surrounded by a cloud of electrons which very slightly shield the nucleus from any external magnetic field. As a structure of the electron cloud is specific to an individual molecule or compound, the magnitude of this screening effect is then also a characteristic of the chemical environment of individual nuclei. In view of the fact that the resonant frequency is proportional to the magnetic field it experiences, the resonant frequency can be determined not only by the external applied field, but also by the small field shift generated by the electron cloud. This shift in frequency is called the chemical shift. It is noted that the chemical shift is a very small effect and is usually expressed as “parts per million” (PPM) of the main frequency. In order to resolve the different chemical species, it is therefore necessary to achieve very high levels of homogeneity of the main magnetic field B0.
In the context of human MRS, two nuclei are of particular interest, H1 and P31. Proton MR spectroscopy is mainly employed in studies of the brain where prominent peaks arise from certain metabolites. Phosphorus 31 MR spectroscopy detects compounds involved in energy metabolism in certain compounds related to membrane synthesis and degradation. Metabolites of particular interest in MRS studies include glutamate (Glu), glutamine (Gln), choline (Cho), creatine (Cre), N-acetylaspartate (NAA), and the inositols (ml and sl).
Glu is the principal excitatory neurotransmitter of the central nervous system. In brain, Glu, Gln, and Glu/Gln-enzymes are compartmentalized within neurons and glial cells (astrocytes). Transient increases in extracellular Glu (Glu0) associated with neruotransmission is important for normal brain function. From the synaptic space, Glu0 is recycled and internalized by glial cells and converted to Gln. This normal cycle prevents glutamate from accumulating in the extracellular compartment where it binds to membrane receptors, such as N-methyl-D-aspartate (NMDA) and ampa-kainate proteins. Prolonged extracellular exposure to high Glu0, however, is toxic. Excess Glu0 in the synaptic space can trigger a toxic cascade, via NMDA receptors, leading to neuronal and non-neuronal (oligodendrocyte) cell death because of excessive accumulation of intracellular calcium, which in turn leads to free radicals and nitric oxide production as well as formation of apoptotic bodies. This neural excitotoxicity cascade might have a key role in a number of neurodegenerative diseases, including MS, AD, ALS, HD, and as a bystander effect in stroke and brain trauma. Even gliomas have been found to respond to glutamate antagonists. Although Glu0 is probably below detectability by whole body 3T MR spectroscopy, intracellular concentrations of both Glu and Gln are high enough for MRS detection. In conventional proton spectra, the overlapped signals of Glu and Gln are readily measured as total Glu+Gln (Glx). Some studies have shown increases in Glx for severe abnormalities such as hypoxic encephalopathy, acute MS lesions, HD, ALS, and certain tumors. Decreases in the Glx signal have also been reported. Unfortunately, Glx does not measure changes in Glu/Gln status, and is therefore unlikely to be an adequate marker for less profound changes in intracellular conditions, which may proceed or accompany conditions of toxic Glu0. Spectral overlap of Gln, Glu, NAA, and ml make it difficult to reliably sort out Glu and Gln individually in conventional spectra.
It would therefore be advantageous to have a technique to provide improved in vivo spectroscopic measurement of metabolites, such as glutamate, glutamine, choline, creatine, N-acetylaspartate and the inositols.